| Previous data from this laboratory demonstrated that increasing [Ca 2+]i stimulates lipogenesis and inhibits basal and agonist-stimulated lipolysis in both human and murine adipocytes. These data suggest that adipocyte [Ca2+]i is a logical target for pharmacological/nutritional regulation of adiposity. Accordingly, our studies were designed to (1) determine the role of [Ca2+]i in human adipocyte differentiation, an important contributor to adiposity, and (2) identify adipocyte targets which regulate [Ca2+]i and determine strategies for modulating these targets. We demonstrated that increasing preadipocyte [Ca2+]i in early stages of differentiation suppresses human adipocyte differentiation, while increasing [Ca2+] i late promotes human adipocyte differentiation. We identified a potential receptor target, the adipocyte sulfonylurea receptor (SUR), which mediates adipocyte [Ca2+]i signaling and corresponding increased lipogenesis and decreased lipolysis. Antagonism of this receptor reverses all these actions. We further extended this approach to dietary regulation of adipocyte [Ca2+]i. We demonstrated that 1α,25-(OH) 2-D3, which is regulated by dietary calcium, also stimulates adipocyte [Ca2+]i, promotes lipogenesis, and inhibits lipolysis, thereby resulting in triglyceride accumulation, via a rapid non-genomic action mediated by a putative membrane vitamin D receptor (mVDR). These actions can be mimicked by 1α,25-(OH)2-lumisterol 3, a specific agonist for mVDR, and completely prevented by 1β,25-(OH) 2-D3, a specific antagonist for the mVDR. Our data father demonstrated that suppression of 1α,25-(OH)2-D3 by increasing dietary calcium decreases adipocyte [Ca2+] i, stimulates lipolysis, inhibits lipogenesis in aP2-agouti transgenic mice and that dietary calcium not only attenuated diet-induced obesity but also accelerated weight loss and fat mass reduction secondary to caloric restriction. Notably, high calcium diets also increased white adipose tissue uncoupling protein 2 (UCP2) expression and core temperature. Subsequently, we demonstrated that 1α,25-(OH)2-D3 exerts an inhibitory effect on white adipocyte UCP2 expression and that this effect is mediated via a genomic action (nuclear vitamin D receptor; nVDR). Accordingly, these data demonstrate that SUR-mediated Ca2+ signaling and 1α,25-(OH) 2-D3-mediated genomic and non-genomic pathways play important roles in regulation of adipocyte lipid and energy metabolism and that antagonism of adipocyte [Ca2+]i by blocking these pathways may represent an effective approach for development of therapeutic intervention in obesity. |
